Polymer-controlled release of tobramycin from bone graft void filler

Abstract

Despite clinical, material, and pharmaceutical advances, infection remains a major obstacle in total joint revision surgery. Successful solutions must extend beyond bulk biomaterial and device modifications, integrating locally delivered pharmaceuticals and physiological cues at the implant site, or within large bone defects with prominent avascular spaces. One approach involves coating clinically familiar allograft bone with an antibiotic-releasing rate-controlling polymer membrane for use as a matrix for local drug release in bone. The kinetics of drug release from this system can be tailored via alterations in the substrate or the polymeric coating. Drug-loaded polycaprolactone coating releases bioactive tobramycin from both cadaveric-sourced cancellous allograft fragments and synthetic hybrid coralline ceramic bone graft fragments with similar kinetics over a clinically relevant 6-week timeframe. However, micron-sized allograft particulate provides extended bioactive tobramycin release. Addition of porogen polyethylene glycol to the polymer coating formulation changes tobramycin release kinetics without significant impact on released antibiotic bioactivity. Incorporation of oil-microencapsulated tobramycin into the polymer coating did not significantly modify tobramycin release kinetics. In addition to releasing inhibitory concentrations of tobramycin, antibiotic-loaded allograft bone provides recognized beneficial osteoconductive potential, attractive for decreasing orthopedic surgical infections with improved filling of dead space and new bone formation.

Comparisons of Release of Several Antibiotics from Antimicrobial Polymer-Coated Allograft Bone Void Filler

“…While tobramycin, gentamicin, and vancomycin remain central clinical candidates, other antibiotics warrant consideration based on their release profiles and "bactericidity", especially ciprofloxacin and rifampicin. Thus, combination devices created by incorporating antibiotics into biomedical degradable polycaprolactone polymer coatings on clinically familiar bone void fillers (10,11) seek to 1) fill dead spaces and facilitate osteoconduction in orthopedic surgical repairs, 2) prevent surgical osteomyelitis, and 3) mitigate possible microbial antibiotic resistance --all necessary for effective treatment and healing.…”

“…Past studies releasing tobramycin from the described polymer-loaded drug delivery system suggest that Polymer-Coated Allograft Bone Void Filler modulation of polymer and graft-coating techniques provides versatility to fabricate combination approaches to minimize bone infections (10,11). The current study demonstrates that the solid formulation of the antibiotic, either as an antibiotic salt or its free-base form, alters drug loading and release profiles based both on polymer and drug solubility, and solvent/solute miscibility parameters.…”

“…This design provides antimicrobial dosing, bioactivity and a level of delivery control unattainable with drug physisorption or soaking reported previously (10,11). Although polymer-controlled local drug delivery to bone is not a new idea (12) successful tailoring of the polymer rate-controlling barrier to provide predictable extended drug release bioactivity coordinated with osteoconduction improves this classic concept (10,11).…”

“…Release studies were conducted as previously described (10,11) with the exception that AABF samples were released into 5mL of 10 mM Phosphate Buffered Saline (PBS) at 37˚C.…”

“…This design provides antimicrobial dosing, bioactivity and a level of delivery control unattainable with drug physisorption or soaking reported previously (10,11). Although polymer-controlled local drug delivery to bone is not a new idea (12) successful tailoring of the polymer rate-controlling barrier to provide predictable extended drug release bioactivity coordinated with osteoconduction improves this classic concept (10,11). The impact of drug solubility and drug-polymer miscibility on bioactivity release profiles from this construct have been studied: water-soluble antibiotics (vancomycin, oxacillin, tobramycin) and water-insoluble antibiotics (ciprofloxacin, rifampicin) were formulated into degradable PCL coatings applied to bone allografts, using either organic solvent/water non-solvent binary solutions or pure organic solutions, and released in vitro.…”